Project Summary Despite the prevalence of the RyR in cardiac function, only a few therapies have been developed for the prevention and treatment of cardiac disease that target the ryanodine receptor (RyR). To determine whether or not such therapies might be developed from the isoryanodane framework, we propose to complete a total synthesis of the natural isoryanodanes perseanol and 18-hydroxyperseanol. Access to the isoryanodanes will position us to assess the ability of these diterpenes to bind to the RyR, specifically, through the preparation of unnatural isoryanodanes bearing the critical pyrrole-2-carboxylate ester. Two highly convergent strategies aimed at efficiently establishing the polycyclic framework of these natural products are detailed. In the first strategy, a Heck cyclization/Stille cross-coupling cascade is proposed. The resulting allyl group serves as a handle to forge the 7- membered D-ring lactone in a two-step sequence involving a highly chemoselective Stahl aerobic oxidation. In the second strategy, a late-stage SmI2-mediated ketyl radical cyclization is envisioned to forge, at once, the C8?C9 bond and a critical all-carbon quaternary center. The development of an efficient and general approach will allow a comprehensive evaluation of these small molecules for the preparation of RyR isoform-selective molecular probes. The result of such a systematic approach will be the ability to rationally design small molecules for the treatment of cardiac disease. In doing so, we believe novel and potentially more effective cardiac treatments will be produced.